PCT Publication No. WO01/47919A1 (corresponding US equivalent U.S. Pat. No. 7,585,860) discloses a variety of substituted oxazolidinone derivatives and their salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds are anticoagulants which inhibit the blood coagulation factor Xa with increased selectivity. Among them, Rivaroxaban, 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl]thiophene-2-carboxamide, acts as inhibitor of clotting factor Xa and which is used as agent for the prophylaxis and/or treatment of thromboembolic disorders, in particular myocardial infarction, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transient ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses. Rivaroxaban is represented by the following structural formula I:

Rivaroxaban is sold by Bayer under the brand name Xarelto® and it is orally administered as tablets containing 10 mg of rivaroxaban.
Various processes for the preparation of rivaroxaban, its intermediates, and related compounds are disclosed in U.S. Pat. Nos. 7,585,860; 7,351,823 and 7,816,355; PCT Publication Nos. WO2011/012321, WO2011/080341 and WO2011/098501; and J. Med. Chem. 2005, 48, 5900-5908.
According to U.S. Pat. No. 7,585,860 (hereinafter referred to as the '860 patent), rivaroxaban is prepared by reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one with 5-chlorothiophene-2-carbonyl chloride in the presences of excess amounts of pyridine. As per the process exemplified in example 44 of the '860 patent, rivaroxaban is prepared by drop-wise addition of 5-chlorothiophene-2-carbonyl chloride to a solution of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one in pyridine at 0° C. under argon, followed by removal of ice-cooling and stirring the reaction mixture at room temperature for 1 hour and then admixing with water. After addition of dichloromethane and phase separation, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried, filtered, and evaporated in vacuo. The residue was purified by Flash chromatography (dichloromethane/methanol mixtures) to produce rivaroxaban.
According to U.S. Pat. No. 7,351,823 (hereinafter referred to as the '823 patent), rivaroxaban is prepared by reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one hydrochloride salt with 5-chlorothiophene-2-carbonyl chloride in the presence of an inorganic base, preferably sodium carbonate, in a solvent selected from the group consisting of ether, alcohol, ketone and water or in a mixture thereof. As per the process exemplified in the '823 patent, the preparation of rivaroxaban is carried out in three steps. According to the first step, 5-chlorothiophene-2-carbonyl chloride is prepared by reacting 5-chlorothiophene-2-carboxylic acid with thionyl chloride in toluene at a temperature of 75 to 80° C. According to the second step, 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one hydrochloride salt is reacted with 5-chlorothiophene-2-carbonyl chloride (30% strength solution in toluene) in the presence of sodium carbonate in a solvent mixture containing water and acetone to produce crude rivaroxaban. In third step, the solvent-containing crude product is purified by recrystallization from acetic acid.
The processes for the preparation of rivaroxaban described in the aforementioned prior art suffer from disadvantages such as the use of highly hazardous materials like thionyl chloride and pyridine, and use of tedious and cumbersome procedures like low temperatures, multiple process steps, column chromatographic purifications, multiple isolations/re-crystallizations, recrystallization using corrosive acids like acetic acid, and thus resulting in a poor product yield and quality. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.
The main drawback of the processes for the preparation of rivaroxaban described in the aforementioned prior art is that the processes involve the use of highly corrosive and unstable acid chloride intermediate, 5-chlorothiophene-2-carbonyl chloride. Use of this unstable acid chloride intermediate is not advisable for scale up operations due to handling difficulties. Moreover, the process for the preparation of the acid chloride intermediate requires the use of highly hazardous and toxic reagents like thionyl chloride, phosgene and oxalyl chloride, which are highly corrosive and dangerous to environment. Handling of these reagents is very difficult on commercial scale operations.
The process for the preparation of rivaroxaban described in the '860 patent involves the use of excess amounts of pyridine, which is highly toxic chemical and dangerous to human health.
Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of rivaroxaban at lab scale and in commercial scale operations.
A need remains for an improved, commercially viable and environmentally friendly process of preparing rivaroxaban with high yield and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include non-hazardous conditions, environmentally friendly and easy to handle reagents, reduced process steps, reduced reaction time periods, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of rivaroxaban in high purity and with high yield.